TRPV4 is one of a cation channel of the TRP (Transient Receptor Potential) superfamily. It was discovered as an osmotic-sensitivity receptor activated by hypotonic stimulus. Then, it was shown that TRPV4 had a temperature-sensitive property, that is, TRPV4 was activated at the body temperature rage, and TRPV4 is activated by heat and low pH. It is reported that the gene and protein of TRPV4 is expressed in brain, spinal code, peripheral nerve fiber, skin, kidney, trachea, cochlea and bone, etc. Moreover, it is also reported that TRPV4 is activated by the compounds, such as arachidonic acid, arachidonate metabolite, endocannabinoids, and phorbol ester. The increase of activation of the C-fiber by hypotonic stimulation under the inflammatory environment induced by inflammatory mediators is known, and it is also reported that TRPV4 relates to this activation. Furthermore, it is also reported that TRPV4 is activated by fluid pressure and mechanical stimuli, and TRPV4 relates to hyperalgesia caused by mechanical stimuli. In addition, it is also reported that TRPV4 relates to paclitaxel-induced pain (Non-patent documents 1 to 5). Therefore, it is expected that TRPV4 participates in many physiological roles. The compound which exhibits high affinity to TRPV4 has a high potential as useful medicine in the therapy and/or prevention of TRPV4 receptor-mediated disorder.
The compounds having TRPV4 inhibitory activity are disclosed in patent-documents 1 to 11, 20 to 25 and non-patent documents 6 to 12. The compounds suggested to be related with TRPV4 are disclosed in patent-documents 12 to 19. However, the compounds of this present invention are not disclosed in any documents.
The derivatives wherein two thiazole rings are directly attached are disclosed in patent-document 26. However, there is neither disclosure nor suggestion about a TRPV4 inhibitory activity.
The compounds having TRPV4 inhibitory activities are disclosed in patent-documents 27, but these compounds which are substantively disclosed have different structures compared to the compound of the present invention.